tbuckley/cabot-search huggingface dataset:
Mesenchymal Stem Cell–mediated Image-guided Sodium Iodide Symporter (<i>NIS</i>) Gene Therapy Improves Survival of Glioblastoma-bearing Mice
Authors: Carolin Kitzberger, Rebekka Spellerberg, Yang Han, Kathrin A. Schmohl, Christina Stauss, Christian Zach, Roland E. Kälin, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Rainer Glass, Wolfgang A. Weber, Ernst Wagner, Peter J. Nelson, Christine Spitzweg
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Mesenchymal stem cells (MSC) have emerged as cellular-based vehicles for the delivery of therapeutic genes in cancer therapy based on their inherent tumor-homing capability. As theranostic gene, the sodium iodide symporter (NIS) represents a successful target for noninvasive radionuclide-based imaging and therapy. In this study, we applied genetically engineered MSCs for tumor-targeted NIS gene transfer in experimental glioblastoma (GBM)—a tumor with an extremely poor prognosis. Experimental Design: A syngeneic, immunocompetent GL261 GBM mouse model was established by subcutaneous and orthotopic implantation. Furthermore, a subcutaneous xenograft U87 model was used. Bone marrow–derived MSCs were stably transfected with a NIS-expressing plasmid driven by the constitutively active cytomegalovirus promoter (NIS-MSC). After multiple or single intravenous injection of NIS-MSCs, tumoral iodide uptake was monitored in vivo using 123I-scintigraphy or 124I-PET. Following validation of functional NIS expression, a therapy trial with 131I was performed on the basis of the most optimal application regime as seen by 124I-PET imaging in the orthotopic approach. Results: A robust tumoral NIS-specific radionuclide accumulation was observed after NIS-MSC and radioiodide application by NIS-mediated in vivo imaging. NIS immunofluorescence staining of GBM and non-target tissues showed tumor-selective MSC homing along with NIS expression. Application of therapeutically effective 131I led to significantly delayed tumor growth and prolonged median survival after NIS-MSC treatment as compared with controls. Conclusions: A strong tumor-selective recruitment of systemically applied MSCs into GBM was found using NIS as reporter gene followed by successful therapeutic application of radioiodide demonstrating the potential use of NIS-based MSCs as therapy vehicles as a new GBM therapy approach.
Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes
Authors: Jian-Jun Liu, Sylvia Liu, Jiexun Wang, Sharon L.T. Pek, Janus Lee, Resham L. Gurung, Keven Ang, Yi Ming Shao, Subramaniam Tavintharan, Wern Ee Tang, Chee Fang Sum, Su Chi Lim
Journal: Diabetes Care (2022)

OBJECTIVE Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-β (TGF-β)–induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) &amp;gt;30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR &amp;lt;15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses. RESULTS During a median follow-up of 8.6 (interquartile range 5.8–9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04–3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19–1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD. CONCLUSIONS Urine LRG1, a TGF-β signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression.
A sandwiched patch toward leakage-free and anti-postoperative tissue adhesion sealing of intestinal injuries
Authors: Wei Yang, Chengkai Xuan, Xuemin Liu, Qiang Zhang, Kai Wu, Liming Bian, Xuetao Shi
Journal: Bioactive Materials (2022)

Ideal repair of intestinal injury requires a combination of leakage-free sealing and postoperative antiadhesion. However, neither conventional hand-sewn closures nor existing bioglues/patches can achieve such a combination. To this end, we develop a sandwiched patch composed of an inner adhesive and an outer antiadhesive layer that are topologically linked together through a reinforced interlayer. The inner adhesive layer tightly and instantly adheres to the wound sites via -NHS chemistry; the outer antiadhesive layer can inhibit cell and protein fouling based on the zwitterion structure; and the interlayer enhances the bulk resilience of the patch under excessive deformation. This complementary trilayer patch (TLP) possesses a unique combination of instant wet adhesion, high mechanical strength, and biological inertness. Both rat and pig models demonstrate that the sandwiched TLP can effectively seal intestinal injuries and inhibit undesired postoperative tissue adhesion. The study provides valuable insight into the design of multifunctional bioadhesives to enhance the treatment efficacy of intestinal injuries.
Doubled-Up Households, Self-Management Behaviors, Diabetes Preventive Care Services, and Hospital Use in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) 2015–2020
Authors: Earle C. Chambers, Simin Hua, Juan Lin, Ryung S. Kim, Marston E. Youngblood, Krista M. Perreira, Linda C. Gallo, Aida L. Giachello, Robert Kaplan, Madeline Crespo-Figueroa, Matthew J. O’Brien, Marc D. Gellman, Carmen R. Isasi
Journal: Diabetes Care (2022)

OBJECTIVE We investigated associations of living in a doubled-up household (i.e., adults living with adult children, other related adults, or other unrelated adults) with diabetes self-management behaviors, occurrence of diabetes preventive care services, and hospital use by Hispanic/Latino adults with diabetes. RESEARCH DESIGN AND METHODS We analyzed data from the second clinical visit (2014–2017) through subsequent annual follow-up interviews completed through January 2020 of all participants with diabetes in the Hispanic Community Health Study/Study of Latinos. Multivariable regression was used to test associations between doubled-up status with diabetes self-management behaviors (i.e., checking blood glucose level, checking feet for sores), diabetes preventive care services done by a doctor (i.e., dilated-eye examination, feet checked, hemoglobin A1c measured, urine analysis for kidney function), and hospital use (i.e., emergency department [ED] visits and hospitalizations). RESULTS Hispanic/Latino adults living doubled up were less likely to have their urine checked by a doctor for kidney disease compared with adults not in doubled-up households. Doubled-up status was not associated with diabetes self-management behaviors. Adults living doubled up in a household with other related adults had a 33% increased risk of ED visits compared with adults living doubled up in a household with adult children. CONCLUSIONS Health care settings where Hispanic/Latino adults with diabetes receive trusted care should add housing characteristics such as doubled-up status to social-needs screening to identify residents in need of connecting with housing or social services and more targeted diabetes management services.
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Authors: Pierre-Paul Axisa, Tomomi M. Yoshida, Liliana E. Lucca, Herbert G. Kasler, Matthew R. Lincoln, Giang H. Pham, Dante Del Priore, Jean-Marie Carpier, Carrie L. Lucas, Eric Verdin, Tomokazu S. Sumida, David A. Hafler
Journal: Science Translational Medicine (2022)

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3 + regulatory T cells (T regs ), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, T reg -specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, T regs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating T regs , as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.
Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis
Authors: Tiffany Shi, Astha Malik, Annika Yang vom Hofe, Louis Matuschek, Mary Mullen, Celine S. Lages, Ramesh Kudira, Ruchi Singh, Wujuan Zhang, Kenneth D.R. Setchell, David Hildeman, Chandrashekhar Pasare, Brandee Wagner, Alexander G. Miethke
Journal: Science Translational Medicine (2022)

Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2 −/− mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1β and TNFα by hepatic macrophages and inhibition of T H 1/T H 17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant T H 1 and T H 17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine–induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1β and IFNγ production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-T H 1/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.
Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice
Authors: Alicja Czopek, Rebecca Moorhouse, Peter J. Gallacher, Dan Pugh, Jessica R. Ivy, Tariq E. Farrah, Emily Godden, Robert W. Hunter, David J. Webb, Pierre-Louis Tharaux, David C. Kluth, James W. Dear, Matthew A. Bailey, Neeraj Dhaun
Journal: Science Translational Medicine (2022)

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C high monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C high monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C low monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.
Targeting cytokines in inflammatory bowel disease
Authors: Markus F. Neurath
Journal: Science Translational Medicine (2022)

Targeting cytokines in inflammatory bowel disease (IBD) is a useful clinical approach. Potential therapies for IBD include regulatory T cell transfer to restore cytokine balance, blocking proinflammatory cytokines (e.g., IL-12 and IL-23) or their receptors (sIL-6R and IL-36R), or inhibiting signaling kinases (e.g., JAK). An emerging trend in IBD therapy is to combine several anti-cytokine agents simultaneously.
Effect of Dapagliflozin on Health Status in Patients With Preserved or Mildly Reduced Ejection Fraction
Authors: Mikhail N. Kosiborod, Ankeet S. Bhatt, Brian L. Claggett, Muthiah Vaduganathan, Ian J. Kulac, Carolyn S.P. Lam, Adrian F. Hernandez, Felipe A. Martinez, Silvio E. Inzucchi, Sanjiv J. Shah, Rudolf A. de Boer, Pardeep S. Jhund, Akshay S. Desai, James C. Fang, Yaling Han, Josep Comin-Colet, Orly Vardeny, Daniel Lindholm, Ulrica Wilderäng, Olof Bengtsson, John J.V. McMurray, Scott D. Solomon
Journal: Journal of the American College of Cardiology (2022)

Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and poor quality of life; improving health status is a key goal of management.In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ).The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ.A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 [95% CI: 0.58-0.84]; 0.81 [95% CI: 0.65-1.01]; 1.07 [95% CI: 0.83-1.37]; Pinteraction = 0.026). Dapagliflozin improved KCCQ-TSS, -PLS, -CSS, and -OSS at 8 months (2.4, 1.9, 2.3, and 2.1 points higher vs placebo; P < 0.001 for all). Dapagliflozin-treated patients experienced improvements in KCCQ-TSS regardless of EF (Pinteraction = 0.85). Fewer dapagliflozin-treated patients had deterioration, and more had improvements in all KCCQ domains at 8 months.The clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
Atrial Longitudinal Strain Predicts New-Onset Atrial Fibrillation
Authors: Matteo Serenelli, Anna Cantone, Beatrice Dal Passo, Luca Di Ienno, Alessio Fiorio, Rita Pavasini, Giulia Passarini, Matteo Bertini, Gianluca Campo
Journal: JACC. Cardiovascular imaging (2022)
Traumatic encephalopathy syndrome: application of new criteria to a cohort exposed to repetitive head impacts
Authors: Aaron Ritter, Guogen Shan, Arturo Montes, Rebekah Randall, Charles Bernick
Journal: British Journal of Sports Medicine (2022)

To examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they show differences in MRI-based regional brain volumes, cognitive domains, and certain plasma biomarkers.Professional fighters 35 years of age or older and/or retired were included. Participants were categorised as either having TES (TES+) or not (non-TES). TES+ participants were further subtyped by their cognitive profile. Multiple linear regression models were used to compare MRI-based regional brain volumes, cognitive performance, plasma tau and neurofilament light levels between TES- and TES+ groups.176 participants (110 boxers and 66 MMA) were included in the analysis. 72 (41%)/176 were categorised as having TES, the likelihood of TES increasing with age. TES+ participants tended to be boxers, started fighting at a younger age, had more professional fights and knocked out more frequently. The TES+ group had lower regional brain volumes including both grey and white matter structures. TES+ also had lower scores on simple and choice reaction time, psychomotor speed and Trails A .The new TES criteria does distinguish a group of fighters with differences in regional brain volumes and reduced cognitive function. Our findings support the use of the NINDS criteria for TES in further research of the long-term effects of repetitive head impacts.
Clinical Characteristics and Prognosis of MINOCA Caused by Atherosclerotic and Nonatherosclerotic Mechanisms Assessed by OCT
Authors: Ming Zeng, Chen Zhao, Xiaoyi Bao, Minghao Liu, Luping He, Yishuo Xu, Wei Meng, Yuhan Qin, Ziqian Weng, Boling Yi, Dirui Zhang, Shengfang Wang, Xing Luo, Ying Lv, Xi Chen, Qianhui Sun, Xue Feng, Zhanqun Gao, Yanli Sun, Abigail Demuyakor, Ji Li, Sining Hu, Giulio Guagliumi, Gary S. Mintz, Haibo Jia, Bo Yu
Journal: JACC. Cardiovascular imaging (2022)
3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy
Authors: Bobak Heydari, Alessandro Satriano, Michael Jerosch-Herold, Paul Kolm, Dong-Yun Kim, Kathleen Cheng, Yuna L Choi, Panagiotis Antiochos, James A White, Masliza Mahmod, Kenneth Chan, Betty Raman, Milind Y Desai, Carolyn Y Ho, Sarahfaye F Dolman, Patrice Desvigne-Nickens, Martin S Maron, Matthias G Friedrich, Jeanette Schulz-Menger, Stefan K Piechnik, Evan Appelbaum, William S Weintraub, Stefan Neubauer, Christopher M Kramer, Raymond Y Kwong
Journal: JACC. Cardiovascular imaging (2022)
Myocardial Work Predicts Outcome in Asymptomatic Severe Aortic Stenosis
Authors: Marko Banovic, Niya Mileva, Ana Moya, Pasquale Paolisso, Monika Beles, Nikola Boskovic, Miodrag Jovanovic, Ivana Nedeljkovic, Anja Radunovic, Marija Radjenovic, Mina Raznatovic, Milica Bojanic, Andrea Manojlovic, Martin Kotrc, Radka Kockova, Guy Van Camp, Marc Vanderheyden, Svetozar Putnik, Bernard Iung, Jozef Bartunek, Martin Penicka
Journal: JACC. Cardiovascular imaging (2022)
Clinical and Coronary Plaque Predictors of Atherosclerotic Nonresponse to Statin Therapy
Authors: Sophie E. van Rosendael, Inge J. van den Hoogen, Fay Y. Lin, Daniele Andreini, Mouaz H. Al-Mallah, Matthew J. Budoff, Filippo Cademartiri, Kavitha Chinnaiyan, Jung Hyun Choi, Edoardo Conte, Hugo Marques, Pedro de Araújo Gonçalves, Ilan Gottlieb, Martin Hadamitzky, Jonathon A. Leipsic, Erica Maffei, Gianluca Pontone, Gilbert L. Raff, Sanghoon Shin, Yong-Jin Kim, Byoung Kwon Lee, Eun Ju Chun, Ji Min Sung, Sang-Eun Lee, Renu Virmani, Habib Samady, Peter H. Stone, James K. Min, Jagat Narula, Leslee J. Shaw, Hyuk-Jae Chang, Alexander R. van Rosendael, Jeroen J. Bax
Journal: JACC. Cardiovascular imaging (2022)
Noninvasive In Vivo Coronary Artery Thrombus Imaging
Authors: Evangelos Tzolos, Rong Bing, Jack Andrews, Mark G. MacAskill, Adriana A.S. Tavares, Gillian Macnaught, Tim Clark, Nicholas L. Mills, Takeshi Fujisawa, Jennifer Nash, Damini Dey, Piotr J. Slomka, Norman Koglin, Andrew W. Stephens, Marcus-Andre Deutsch, Edwin J.R. van Beek, Michelle C. Williams, Sven Hermann, Verena Hugenberg, Marc R. Dweck, David E. Newby
Journal: JACC. Cardiovascular imaging (2022)
Benefits of an OCT-Based Reperfusion Strategy in STEMI
Authors: Luping He, Dirui Zhang, Yishuo Xu, Sining Hu, Yongfeng Shi, Lei Zhao, Yanqing Wu, Zhiqi Sun, Yin Liu, Lulu Li, Ziqian Weng, Xue Feng, Tao Chen, Xiling Zhang, Yining Yang, Jianping Li, Jingbo Hou, Bin Liu, Gary S. Mintz, Haibo Jia, Bo Yu
Journal: JACC. Cardiovascular imaging (2022)
Aortic Stenosis Progression
Authors: Nadav Willner, Graeme Prosperi-Porta, Lawrence Lau, Angel Yi Nam Fu, Kevin Boczar, Anthony Poulin, Pietro Di Santo, Rudy R. Unni, Sarah Visintini, Paul E. Ronksley, Kwan-Leung Chan, Luc Beauchesne, Ian G. Burwash, David Messika-Zeitoun
Journal: JACC. Cardiovascular imaging (2022)